Pancreatic Cancer in Hereditary Breast and Ovarian Cancer Syndrome: Is Early Detection Possible?

Kodai Abe; Minoru Kitago; Yusuke Kobayashi; Kenta Masuda; Tomoko Seki; Mamiko Yamada; Yumiko Goto; Ikumi Ono; Kumiko Misu; Kohei Nakamura; Yuko Kitagawa

doi:10.2302/kjm.2024-0018-OA

Abstract

A program of recruiting families with hereditary pancreatic cancer and hereditary breast and ovarian cancer (HBOC) syndrome as high-risk individuals for pancreatic cancer surveillance using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) has proven effective, resulting in the improvement of early detection rates and life expectancy. Given this, recent guidelines recommend pancreatic surveillance for patients with familial pancreatic cancer and pathological variants of ten genes, including BRCA1/2. In April 2021, our hospital established the HBOC Center, which is operated by nine departments, including obstetrics and gynecology, breast surgery, pancreatology, urology, medical genetics, dermatology, psychiatry and neurology, and oncology. Currently, MRCP or EUS is performed once or twice a year in 63 cases with pathogenic variants in 54 families. Although 4 cases (6.3%) revealed pancreatic microcysts or branched intraductal papillary mucinous neoplasms, no sign of pancreatic cancer was detected. Since January 2021, the germline BRCA1/2 test for companion diagnosis of pancreatic cancer has been covered by insurance, improving the accessibility of genetic testing among patients with pancreatic cancer. However, the BRCA1/2 positivity rate remains low at 1.3%, and its indication for use is very limited. The implementation of genetic testing, including BRCA1/2 analysis, is necessary for the prevention and early detection of pancreatic cancer in high-risk families.

Introduction

The pancreas is a horizontally elongated, solid organ located in the upper left abdomen, posterior to the stomach. It is approximately 18 cm long, 3–6 cm wide, and 1–3 cm thick, with an average weight of 80 g. The pancreas is divided into the head, which is surrounded by the duodenum, and the body and tail. Additionally, the dorsal surface of the pancreas is traversed by major blood vessels, including the portal vein, aorta, and inferior vena cava (Fig. 1).

Fig. 1

Anatomical and biological features of the pancreas.

The pancreas is surrounded by the duodenum and is located anterior to the superior mesenteric artery and vein. The pancreas performs exocrine and endocrine functions related to food digestion and glycemic control.

The pancreas serves a dual role, functioning both as an exocrine and endocrine organ. Exocrine cells produce digestive enzymes, such as amylase and trypsin, whereas endocrine cells produce blood glucose hormones, such as insulin and glucagon. Consequently, pancreatic dysfunction, as seen in pancreatitis and surgical resection, can impair exocrine and endocrine functions, resulting in indigestion and diabetes mellitus.

Epidemiology of Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer death globally, following only lung, colorectal, and stomach cancers, and the number of deaths continues to increase annually. In 2020, the disease claimed 37,677 lives, representing nearly 10% of the total cancer deaths that year (Fig. 2).¹ At that time, projections for 2021 anticipated 44,000 new cases, with expectations of higher pancreatic cancer-related mortality when compared with other cancers. Considering the statistical division of colorectal cancer into colon and rectal cancer based on sex, pancreatic cancer ranks third in males (first is lung cancer, second is stomach cancer) and second in females (first is lung cancer).¹ Furthermore, the number of pancreatic cancer deaths is expected to increase not only in Japan but also worldwide, especially in Asia.²

Fig. 2

Epidemiology and prognosis of pancreatic cancer.

The number of patients diagnosed with pancreatic cancer in 2019 was 43,865, which was approximately 4.4% of all patients with cancer. The majority were diagnosed as Stage III (19%) or Stage IV (47%), resulting in the deaths of 37,677 patients and a relative 5-year overall survival rate of 8.5%.

According to statistics from the National Cancer Center in Japan, the 5-year survival rate of all cancers is reported to be 64.1%.³ Some cancers, such as those in the spectrum of hereditary breast and ovarian cancer (HBOC) syndrome, show good prognoses that emphasize the curability of the disease, with considerably higher survival rates in breast cancer (92.3%), ovarian cancer (60.3%), and prostate cancer (99.1%). However, pancreatic cancer demonstrates a poor survival rate of 8.5% (8.9% in males, 8.1% in females), underscoring its intractability and immense burden on patients and medical professionals.³

According to the Japan Pancreatic Association, in 2012, the survival rate of pancreatic cancer differed depending on cancer staging.⁴ The 5-year survival rate from Stage 0 to Stage IV ranged from 85.8% to 2.7%, correlating higher staging with poorer outcomes.⁴ Although localized disease confined to the pancreas offers a relatively good prognosis (Stages 0 and I), the prognosis becomes overwhelmingly poor for advanced stages that spread beyond the organ (Stage II, Stage III with severe vascular invasion, and Stage IV with distant metastasis).

However, given that only 33.4% of all pancreatic cancers are detected at Stage II or earlier, there are missed opportunities to improve patient outcomes.⁴ This emphasizes the urgent need for robust early detection strategies and potential revisions to existing social systems.

Risk Factors for Developing Pancreatic Cancer

Various risk factors for pancreatic cancer have been reported. As stated in the 2022 Guidelines for Pancreatic Cancer Treatment, lifestyle-related diseases (such as obesity and diabetes), chronic pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) are well-known risk factors for the development of pancreatic cancer.⁵ Despite these findings, the cause of pancreatic cancer remains unknown. As such, there are no definitive preventive measures for pancreatic cancer like those used for stomach cancer (eradication of Helicobacter pylori) or liver cancer (antiviral therapy).

However, recent advancements have been made in early detection systems and genetic-based preventive strategies, among which “pancreatic surveillance in HBOC syndrome” has attracted particular attention. This focus was brought about by findings of epidemiological studies showing familial clustering of pancreatic cancer. A large-cohort prospective epidemiological study conducted by Johns Hopkins University in 2004 showed 4.5-fold, 6.4-fold, and 32-fold increases in lifetime risk of pancreatic cancer for individuals with one, two, and three first-degree relatives (FDRs) with pancreatic cancer, respectively.⁶ Based on these results, we defined “familial pancreatic cancer” as a disease that occurs in a family with two or more close relatives diagnosed with pancreatic cancer. Indeed, familial pancreatic cancer encompasses approximately 5%–10% of all cases.⁷ Beyond familial clustering, pancreatic cancer with germline mutation genes related to hereditary tumors is categorized as “hereditary pancreatic cancer,” with HBOC syndrome as the most prevalent form. Other hereditary tumor syndromes with a particularly high risk of developing pancreatic cancer include Peutz-Jeghers syndrome and familial atypical multiple mole melanoma (FAMMM), followed by Lynch syndrome and familial adenomatous polyposis, which are moderately susceptible to pancreatic cancer.⁸

Recognizing the potential for early intervention, Johns Hopkins University initiated a rigorous surveillance of these conditions, employing endoscopic ultrasound (EUS) and/or magnetic resonance imaging examinations once or twice annually.⁹ Over a period of approximately 5.5 years, 354 subjects have been examined; 14 (3.95%) were found to have pancreatic cancer, and 10 of them underwent surgery. The 5-year survival rate of patients diagnosed by this surveillance was 60%, exceeding that of unscreened individuals. This highlights the utility of such strategies for high-risk individuals.¹⁰ Based on these findings, the National Cancer Comprehensive Network guidelines, since 2019, have recommended annual or biannual EUS and/or magnetic resonance cholangiopancreatography (MRCP) for patients with familial and hereditary pancreatic cancers.¹¹

Management of HBOC Syndrome at our Institute

Pursuant to the campaign against pancreatic cancer, our institute established a dedicated HBOC Center in April 2021 (https://www.hosp.keio.ac.jp/annai/shinryo/hboc-center/). This multidisciplinary group comprises experts belonging to the centers of breast surgery, obstetrics and gynecology, gastroenterological surgery, urology, dermatology, psychiatry and neurology, oncology, and medical genetics. The HBOC Center holds a monthly conference to discuss cases of HBOC syndrome and to establish surveillance for BRCA1/2 pathogenic variant carriers. Tailored protocols are utilized in surveillance protocols depending on sex and type of cancer. To properly administer these protocols and reduce physical, mental, and financial burdens in affected individuals, the center has established a BRCA1/2 pathogenic variant surveillance network.

Pancreatic Surveillance for HBOC Syndrome

Surveillance of the pancreas, mammary glands, and ovaries is recommended for individuals belonging to families with HBOC syndrome.¹² Initial screening typically involves carbohydrate antigen 19–9 (CA19-9) measurement and abdominal ultrasonography. However, given the limited diagnostic accuracy of these methods, EUS and/or MRCP are preferred for families with HBOC or a history of familial pancreatic cancer. At our institute, 54 families and 63 patients underwent pancreatic screening in our outpatient clinic from 1 January 2018 to 31 December 2022. Although the majority of patients carried BRCA1 (27 cases) and BRCA2 (26 cases) pathogenic variants, we also followed up individuals with ATM (7 cases) and PALB2 (3 cases) pathogenic variants according to established BRCA1/2 surveillance protocols. The median age was 50 (34–81) years, and women were predominant (5 men and 58 women) in this cohort, showing a trend toward relatively young morbid variant holders. Although the latest HBOC syndrome guidelines recommend surveillance initiation at age 50 years or older, with annual combined EUS and MRCP for cases aged over 50 years,¹³ frequent pancreatic screening and additional breast and ovarian surveillance for individuals in their 40s often cause considerable physical and mental stress, which induce anxiety for the future. For this reason, we adopted a modified approach for patients under 50 years of age. Specifically, alternation of annual EUS/MRCP examinations and CA19-9 measurement would be indicated for cases without abnormal findings on initial EUS or MRCP (Fig. 3). To date, 4 cases (6.3%) of pancreatic microcysts or branched-type IPMN have been found during surveillance, but fortunately, no case of pancreatic cancer has been observed. Given that pancreatic microcysts and IPMNs are high-risk factors for the development of pancreatic cancer in patients with familial or hereditary pancreatic cancer, sustainable surveillance is essential for these cases.

Fig. 3

Pancreatic surveillance at our institute for HBOC syndrome.

(a) For patients older than 50 years, we performed EUS and/or MRCP and/or CA19-9 twice a year. (b) For patients younger than 50 years or for those refusing active surveillance, we proposed annual EUS or MRCP and/or CA19-9 if there were no abnormal findings in the pancreas. EUS, endoscopic ultrasonography; MRCP, magnetic resonance cholangiopancreatography; CA19-9, carbohydrate antigen 19-9.

HBOC Syndrome and Pancreatic Cancer

Since January 2021, insurance coverage for BRACAnalysis (Myriad, Salt Lake City, UT, USA) has facilitated its utilization as a companion diagnostic test for pancreatic cancer. As of March 2023, the BRACAnalysis data collected at our hospital revealed that 12 (25.0%) of 48 ovarian cancer cases, 9 (9.7%) of 93 breast cancer cases, 1 (12.5%) of 8 prostate cancer cases, and 1 (1.5%) of 68 pancreatic cancer cases were identified as carrying BRCA1/2 pathogenic variants. This underscores the significantly lower number of positive pancreatic cancer cases when compared with other types of cancer. Additionally, the turnaround time, defined as the time for the results to be disclosed, is particularly crucial and remains to be addressed, especially for cases with poor prognosis.¹⁴

Importantly, some germline pathogenic variants beyond BRCA1/2, such as PALB2, ATM, and NBN, have been reported in association with HBOC syndrome. Therefore, multigene panel testing should be considered even if BRACAnalysis results are negative. Furthermore, poly ADP-ribose polymerase inhibitors are only indicated as maintenance therapy following platinum therapy for unresectable metastatic pancreatic cancer,¹⁵ and no clinical trial has been reported to support the expansion of their indication.

Conclusion

Recent years have witnessed significant strides in standardizing HBOC management through the publication of comprehensive guidelines, resulting in the improved care of patients with HBOC and carriers of pathological variants. However, pancreatic cancer within the HBOC spectrum remains challenging because of its refractory nature. Effective diagnostic and therapeutic methods that are comparable with those established for breast and ovarian cancer are desired. To this end, the development of innovative diagnostic and surveillance tools specifically tailored to HBOC-associated pancreatic cancer holds immense promise for enabling early detection and improving patient outcomes.

Acknowledgments

We thank Kazumasa Fukuda, a staff member of the Department of Surgery at Keio University School of Medicine, for his help in preparing this manuscript. We also thank Editage (www.editage.com) for English language editing.

Conflicts of Interest

The authors have declared that no conflict of interest exists.

References

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